title: 3-O-(E)-p-coumaroyl tormentic acid from Eriobotrya japonica leaves induces caspase-dependent apoptotic cell death in human leukemia cell line.
abstract: Eleven triterpene acids, 1-11, isolated from the leaves of Eriobotrya japonica, were evaluated for inhibition of DNA topoisomerase (Topo) I and cytotoxicity against human leukemia (HL60) and melanoma cell lines (CRL1579). Among the compounds tested, four compounds, δ-oleanolic acid (4), ursolic acid (5), 3-O-(E)-p-coumaroyl tormentic acid (8), and betulinic acid (10), exhibited potent Topo I inhibitory activity (IC(50) 20.3-36.5 µM) and cytotoxicity against HL60 (EC(50) 5.0-8.1 µM). Upon assessing the apoptosis-inducing activity in HL60 cells, compound 8 exhibited induction of apoptosis detected by the observation of DNA fragmentation and membrane phospholipid exposure in flow cytometry. Western blot analysis showed that compound 8 markedly reduced the levels of procaspases-3 and 9, while being increased the levels of cleaved caspases-3 and 9. On the other hand, compound 8 exerted almost no influence on the expression of caspase-8. In addition, compound 8 increased significantly Bax/Bcl-2 ratio and activated caspase-2. These results suggested that compound 8 induced apoptotic cell death in HL60 via mainly mitochondrial pathway by, at least in part, Topo I inhibition. Therefore, compound 8 may be promising lead compound for developing an effective drug for treatment of leukemia.
authors.affiliation: College of Science and Technology, Nihon University, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kikuchi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Akazawa
authors.forename: Keiichi
authors.initials: K
authors.lastname: Tabata
authors.forename: Aranya
authors.initials: A
authors.lastname: Manosroi
authors.forename: Jiradej
authors.initials: J
authors.lastname: Manosroi
authors.forename: Takashi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Akihisa
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000302:isolation & purification / Q000633:toxicity; D017209:Apoptosis; D053143:Caspase 2 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D003374:Coumarins / Q000737:chemistry* / Q000302:isolation & purification / Q000633:toxicity; D004264:DNA Topoisomerases, Type I / Q000737:chemistry* / Q000378:metabolism; D031983:Eriobotrya / Q000737:chemistry*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D018515:Plant Leaves / Q000737:chemistry; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D059004:Topoisomerase I Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000633:toxicity; D014315:Triterpenes / Q000737:chemistry* / Q000302:isolation & purification / Q000633:toxicity; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C558720:3-O-(E)-p-coumaroyl tormentic acid; D000972:Antineoplastic Agents, Phytogenic; D003374:Coumarins; D019253:Proto-Oncogene Proteins c-bcl-2; D059004:Topoisomerase I Inhibitors; D014315:Triterpenes; D051028:bcl-2-Associated X Protein; D053143:Caspase 2; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D004264:DNA Topoisomerases, Type I